U.S. patent application number 10/518732 was filed with the patent office on 2005-10-06 for administration of therapeutic viruses.
This patent application is currently assigned to Wellstat Biologics Corporation. Invention is credited to Lorence, Robert M.
Application Number | 20050220818 10/518732 |
Document ID | / |
Family ID | 30000590 |
Filed Date | 2005-10-06 |
United States Patent
Application |
20050220818 |
Kind Code |
A1 |
Lorence, Robert M |
October 6, 2005 |
Administration of therapeutic viruses
Abstract
Two or more desensitization doses of a therapeutic virus are
administered, followed by one or more escalated doses of the virus.
In addition, the rate at which a therapeutic virus is administered
can be controlled.
Inventors: |
Lorence, Robert M;
(Bethesda, MD) |
Correspondence
Address: |
Lewis J. Kreisler
Legal Department
930 Clopper Road
Gaithersburg
MD
20878
US
|
Assignee: |
Wellstat Biologics
Corporation
930 Clopper Road
Gaithersburg
MD
20878
|
Family ID: |
30000590 |
Appl. No.: |
10/518732 |
Filed: |
December 20, 2004 |
PCT Filed: |
May 22, 2003 |
PCT NO: |
PCT/US03/16474 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60390632 |
Jun 21, 2002 |
|
|
|
Current U.S.
Class: |
424/214.1 |
Current CPC
Class: |
A61K 38/2013 20130101;
A61K 38/21 20130101; G01N 33/5011 20130101; A61K 2039/505 20130101;
A61K 38/191 20130101; C12N 2760/18132 20130101; C07K 16/241
20130101; A61P 35/00 20180101; A61K 2039/545 20130101; C12N 7/00
20130101; A61K 39/42 20130101; C12N 2760/18151 20130101; A61K
35/768 20130101 |
Class at
Publication: |
424/214.1 |
International
Class: |
A61K 039/17 |
Claims
1. A method for administering a therapeutic virus to a subject in
one or more cycles, wherein at least one cycle comprises
administering sequentially two or more desensitization doses of the
virus followed by administering one or more escalated doses of the
virus, wherein: the virus is a negative-stranded RNA virus; the
amount of the virus in the second and any subsequent
desensitization dose is not less than the amount of the virus in
the preceding desensitization dose; and the amount of the virus in
each of the one or more escalated doses is higher than the amount
of virus in each of the desensitization doses.
2. The method of claim 1, wherein the virus is a
replication-competent oncolytic virus.
3. The method of claim 2, wherein the oncolytic virus is a
Paramyxovirus.
4. The method of claim 3, wherein the Paramyxovirus is a Newcastle
Disease Virus.
5. The method of claim 4, wherein the virus is a mesogenic strain
of Newcastle Disease Virus.
6. The method of claim 5, wherein the first desensitizing dose is
at least 1.times.10.sup.8 PFU per square meter of patient surface
area.
7-8. (canceled)
9. The method of claim 5, wherein the second desensitizing dose is
at least 3.times.10.sup.9 PFU per square meter of patient surface
area.
10-11. (canceled)
12. The method of claim 5, wherein the escalated doses are each at
least 3.times.10.sup.9 PFU per square meter of patient surface
area.
13-16. (canceled)
17. The method of claim 16, wherein the escalated doses are at
least 9.6.times.10.sup.10 PFU per square meter of patient surface
area.
18-20. (canceled)
21. The method of claim 5, wherein the number of desensitization
doses administered is two.
22. The method of claim 5, wherein the number of desensitization
doses administered is at least three.
23. The method of claim 22, wherein the third desensitization dose
is at least 3.times.10.sup.9 PFU per square meter of patient
surface area.
24-25. (canceled)
26. The method of claim 5, wherein the first desensitization dose:
is administered over an administration time period of up to 24
hours; and is administered at a rate of up to 3.0.times.10.sup.9
PFU per square meter of patient surface area in any ten minute
sampling time period within the administration time period.
27. The method of claim 26, wherein the rate is up to
6.7.times.10.sup.8 PFU per square meter of patient surface area in
any ten minute sampling time period within the administration time
period.
28. The method of claim 27, wherein the rate is up to
3.3.times.10.sup.8 PFU per square meter of patient surface area in
any ten minute sampling time period within the administration time
period.
29. The method of claim 5, wherein one or more doses selected from
the second desensitization dose, any subsequent desensitization
dose and an escalated dose: is administered over an administration
time period of less than 24 hours; and is administered at a rate of
up to 5.0.times.10.sup.10 PFU per square meter of patient surface
area in any ten minute sampling time period within the
administration time period.
30. The method of claim 29, wherein the rate is up to
2.0.times.10.sup.10 PFU per square meter of patient surface area in
any ten minute sampling time period within the administration time
period.
31. The method of claim 2, wherein the oncolytic virus is a
Rhabdovirus.
32. The method of claim 31, wherein the Rhabdovirus is a Vesicular
Stomatitis Virus.
33. The method of claim 1, wherein the amount of the virus in the
second and any subsequent desensitization dose is greater than the
amount of the virus in the preceding desensitization dose.
34. The method of claim 1, wherein the virus is administered to the
subject intravenously.
35-36. (canceled)
37. A method for administering a dose of a therapeutic virus to a
subject, wherein: the virus is a negative-stranded RNA virus; the
dose is the first dose in a cycle comprising one or more doses of
the virus; the dose is administered over an administration time
period of up to 24 hours; and the dose is administered at a rate of
up to 3.0.times.10.sup.9 PFU per square meter of patient surface
area in any ten minute sampling time period within the
administration time period.
38-51. (canceled)
52. A method for administering a dose of a therapeutic virus to a
subject, wherein: the virus is a negative-stranded RNA virus; the
dose is the second or subsequent dose in a cycle comprising two or
more doses of the virus; the dose is administered over an
administration time period of up to 24 hours; and the dose is
administered at a rate of up to 5.0.times.10.sup.10 PFU per square
meter of patient surface area in any ten minute sampling time
period within the administration time period.
53-71. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] Therapeutic viruses (either oncolytic viruses or
replication-incompetent viruses for gene therapy) are used for the
treatment of cancer and other diseases (Kirn, et al., Trends Mol.
Med., 8(4) (Suppl.):S68-S73, 2002 (review)). However the
administration of therapeutic viruses is associated with certain
toxic effects, which limit the amount of virus that can be
administered. (Pecora, et al., J. Clin Oncol. (May 2002)
20(9):2251-2266.)
[0002] The administration of a desensitizing dose of an oncolytic
virus before higher subsequent doses is disclosed in WO 00/62735
(pages 35-36). See also Pecora, et al., J. Clin. Oncol. (May 2002)
20(9):2251-2266; and Bergsland, et al., J. Clin. Oncol. (May 2002)
20(9): 2220-2222.
[0003] The administration of oncolytic viruses using an intravenous
pump, syringe pump, intravenous drip or slow injection over the
course of 4 minutes to 24 hours, for example over the course of 20
to 60 minutes, is disclosed in WO 00/62735 (page 36, lines
16-19).
[0004] It would be desirable to find means of further minimizing
such negative side effects. The minimization side effects is
valuable in its own right, and also because it could make possible
the administration of higher doses of the theraepeutic virus, and
with such higher doses the possibility of improved therapeutic
effect.
SUMMARY OF THE INVENTION
[0005] This invention provides a method for administering a
therapeutic virus to a subject in one or more cycles, wherein at
least one cycle comprises administering sequentially two or more
desensitization doses of the virus followed by administering one or
more escalated doses of the virus, wherein: the virus is a
negative-stranded RNA virus; the amount of the virus in the second
and any subsequent desensitization dose is not less than the amount
of the virus in the preceding desensitization dose; and the amount
of the virus in each of the one or more escalated doses is higher
than the amount of virus in each of the desensitization doses.
[0006] This invention provides a method for administering a dose of
a therapeutic virus to a subject, wherein: the virus is a
negative-stranded RNA virus; the dose is the first dose in a cycle
comprising one or more doses of the virus; the dose is administered
over an administration time period of up to 24 hours; and the dose
is administered at a rate of up to 3.0.times.10.sup.9 PFU per
square meter of patient surface area in any ten minute sampling
time period within the administration time period.
[0007] This invention provides a method for administering a dose of
a therapeutic virus to a subject, wherein: the virus is a
negative-stranded RNA virus; the dose is the second or subsequent
dose in a cycle comprising two or more doses of the virus; the dose
is administered over an administration time period of up to 24
hours; and the dose is administered at a rate of up to
5.0.times.10.sup.10 PFU per square meter of patient surface area in
any ten minute sampling time period within the administration time
period.
[0008] This invention is based on the finding that the toxicities
of a therapeutic virus, for example a mesogenic strain of Newcastle
Disease Virus, can be decreased by at least two introductory
desensitization doses of the virus. It is also based on the finding
that such toxicities can be decreased by limiting the rate at which
the virus is administered.
DETAILED DESCRIPTION OF THE INVENTION
[0009] As used herein the transitional term "comprising" is
open-ended A claim utilizing this term can contain elements in
addition to those recited in such claim. Thus, for example, the
claims can read on treatment regimens that also include other
theapeutic agents or therapeutic virus doses not specifically
recited therein, as long as the recited elements or their
equivalent are present.
[0010] As used herein "NDV" is an abbreviation for Newcastle
Disease Virus. As used herein "DLT" is an abbreviation for dose
limiting toxicity. As used herein the term "plaque-forming unit"
(PFU) means one infectious virus particle. As used herein "BPFU"
means billion PFUs. As used herein "PP" means plaque-purified.
Thus, for example PPMK107 means plaque-purified Newcastle Disease
virus strain MK107. As used herein "PFU/m.sup.2", which is a
standard unit for expressing dosages, means PFUs per square meter
of patient surface area. As used herein the term
"replication-competent" virus refers to a virus that produces
infectious progeny in cancer cells.
[0011] In accordance with the methods of this invention the
therapeutic virus utilized can be of low (lentogenic), moderate
(mesogenic) or high (velogenic) virulence. The level of virulence
is determined in accordance with the Mean Death Time in Eggs (MDT)
test. (Alexander, "Chapter 27: Newcastle Disease" in Laboratory
Manual for the Isolation and Identification of Avian Pathogens,
3.sup.rd ed., Purchase, et al. eds. (Kendall/Hunt, Iowa), page
117.) Viruses are classified by the MDT test as lentogenic
(MDT>90 hours); mesogenic (MDT from 60-90 hours); and velogenic
(MDT<60 hours).
[0012] In accordance with the multi-step desensitization method of
this invention, a regimen comprising two or more desensitization
doses followed by one or more escalated doses can be carried out in
one or more than one treatment cycle. Preferably such
desensitization regimen is followed for at least the first cycle of
treatment, and more preferably for all cycles of treatment.
[0013] In accordance with the multi-step desensitization method of
this invention, the method can be utilized with any conventional
therapy utilizing a therapeutic virus. Examples of such therapies
include oncolytic viruses for the treatment of cancer and the use
of viruses in gene therapy, as described for example in WO
94/25627, WO 00/62735, and Kirn, et al., Trends Mol. Med., 8(4)
(Suppl.):S68-S73, 2002 (review). In one embodiment of the method
the virus is a replication-competent oncolytic virus. In a more
specific embodiment it is a Paramyxovirus, for example a Newcastle
Disease Virus. When utilizing a replication-competent Newcastle
Disease Virus, a mesogenic strain is preferred. In another
embodiment the oncolytic virus is a Rhabdovirus, for example a
Vesicular Stomatitis Virus.
[0014] In progressively more specific embodiments of the multi-step
desensitization method of this invention, and especially when the
virus is a replication-competent, mesogenic strain of NDV, the
first desensitizing dose is at least 1.times.10.sup.8 PFU per
square meter of patient surface area; at least 3.times.10.sup.8 PFU
per square meter of patient surface area; or at least
1.times.10.sup.9 PFU per square meter of patient surface area. In
progressively more specific embodiments of the multi-step
desensitization method of this invention, and especially when the
virus is a replication-competent, mesogenic strain of NDV, the
second desensitizing dose is at least 3.times.10.sup.9 PFU per
square meter of patient surface area; at least 5.9.times.10.sup.9
PFU per square meter of patient surface area; or at least
1.2.times.10.sup.10 PFU per square meter of patient surface area.
In progressively more specific embodiments of the multi-step
desensitization method of this invention, and especially when the
virus is a replication-competent, mesogenic strain of NDV, the
escalated doses are at least 3.times.10.sup.9 PFU per square meter
of patient surface area; at least 5.9.times.10.sup.9 PFU per square
meter of patient surface area; at least 1.2.times.10.sup.10 PFU per
square meter of patient surface area; at least 2.4.times.10.sup.10
PFU per square meter of patient surface area; at least
4.8.times.10.sup.10 PFU per square meter of patient surface area;
at least 9.6.times.10.sup.10 PFU per square meter of patient
surface area; at least 1.2.times.10.sup.11 PFU per square meter of
patient surface area; at least 1.44.times.10.sup.11 PFU per square
meter of patient surface area; or at least 1.96.times.10.sup.11 PFU
per square meter of patient surface area.
[0015] In accordance with the multi-step desensitization method of
this invention, there is no upper limit on the number of
desensitization doses that can be administered. In specific
embodiments of the invention the number of desensitization doses
administered is two or three. In progressively more specific
embodiments of the multi-step desensitization method of this
invention in which at least three doses are administered, and
especially when the virus is a replication-competent, mesogenic
strain of NDV, the third desensitization dose is at least
3.times.10.sup.9 PFU per square meter of patient surface area; at
least 5.9.times.10.sup.9 PFU per square meter of patient surface
area; or at least 1.2.times.10.sup.10 PFU per square meter of
patient surface area.
[0016] In an embodiment of the multi-step desensitization method of
this invention, multi-step desensitization can be combined with
controlled-rate administration of a given dose of the therapeutic
virus. Thus, in accordance with an embodiment of the multi-step
desensitization method of this invention, the first desensitization
dose: is administered over an administration time period of up to
24 hours; and is administered at a rate of up to 3.0.times.10.sup.9
PFU per square meter of patient surface area in any ten minute
sampling time period within the administration time period. In
progressively more specific embodiments, the first desensitization
dose is administered at a rate of up to 6.7.times.10.sup.8 PFU per
square meter of patient surface area in any ten minute sampling
time period within the administration time period; or up to
3.3.times.10.sup.8 PFU per square meter of patient surface area in
any ten minute sampling time period within the administration time
period. In another embodiment of the multi-step desensitization
method of this invention, one or more doses selected from the
second desensitization dose, a subsequent desensitization dose, if
any, and an escalated dose: is administered over an administration
time period of less than 24 hours; and is administered at a rate of
up to 5.0.times.10.sup.10 PFU per square meter of patient surface
area in any ten minute sampling time period within the
administration time period. In a more specific embodiment, the
second desensitization dose, a subsequent desensitization dose or
an escalated dose is administered at a rate of up to
2.0.times.10.sup.10 PFU per square meter of patient surface area in
any ten minute sampling time period within the administration time
period.
[0017] In accordance with the multi-step desensitization method of
this invention, the amount of the virus in the second and any
subsequent desensitization dose can be equal to or, preferably,
greater than the amount of the virus in the preceding
desensitization dose.
[0018] In accordance with the multi-step desensitization method of
this invention, the therapeutic virus can be administered by any
conventional route, for example those disclosed in WO 00/62735.
Intravenous administration is preferred.
[0019] In accordance with the multi-step desensitization method of
this invention, the subject can be a human or a non-human
mammal.
[0020] In accordance with methods of this invention in which the
rate of administration of a therapeutic virus dose is controlled,
the method can be utilized with any conventional therapy utilizing
a therapeutic virus. Examples of such therapies include oncolytic
viruses for the treatment of cancer and the use of viruses in gene
therapy, as described for example in WO 94/25627, WO 00/62735, and
Kirn, et al., Trends Mol. Med., 8(4) (Suppl.):S68-S73, 2002
(review). In one embodiment of the method the virus is a
replication-competent oncolytic virus. In a more specific
embodiment it is a Paramyxovirus, for example a Newcastle Disease
Virus. When utilizing a replication-competent Newcastle Disease
Virus, a mesogenic strain is preferred. In another embodiment the
oncolytic virus is a Rhabdovirus, for example a Vesicular
Stomatitis Virus.
[0021] In accordance with methods of this invention in which the
rate of administration of a therapeutic virus dose is controlled,
the therapeutic virus can be administered by any conventional
route, for example those disclosed in WO 00/62735. Intravenous
administration is preferred.
[0022] In accordance with methods of this invention in which the
rate of administration of a therapeutic virus dose is controlled,
the subject can be a human or a non-human mammal.
[0023] In accordance with methods of this invention in which the
rate of administration of a therapeutic virus dose is controlled,
the administration time period is from 1 hour to 24 hours. In a
more specific embodiment, the administration time period is from 3
hours to 24 hours.
[0024] In progressively more specific further embodiments of the
method of this invention in which the rate of administration of the
first dose in a cycle of the therapeutic virus is controlled, and
especially when the virus is a replication-competent, mesogenic
strain of Newcastle Disease Virus, the rate of the first dose is up
to 6.7.times.10.sup.8 PFU per square meter of patient surface area
in any ten minute sampling time period within the administration
time period; or up to 3.3.times.10.sup.8 PFU per square meter of
patient surface area in any ten minute sampling time period within
the administration time period. In progressively more specific
further embodiments of the method of this invention in which the
rate of administration of the first dose of the therapeutic virus
is controlled, and especially when the virus is a
replication-competent, mesogenic strain of Newcastle Disease Virus,
the amount of virus in the first dose is at least 1.times.10.sup.8
PFU per square meter of patient surface area; at least
3.times.10.sup.8 PFU per square meter of patient surface area; or
at least 1.times.10.sup.9 PFU per square meter of patient surface
area.
[0025] In a more specific further embodiment of the method of this
invention in which the rate of administration of the second or
subsequent dose in a cycle of the therapeutic virus is controlled,
and especially when the virus is a replication-competent, mesogenic
strain of Newcastle Disease Virus, the rate of the second or
subsequent dose is up to 2.0.times.10.sup.10 PFU per square meter
of patient surface area in any ten minute sampling time period
within the administration time period. In progressively more
specific further embodiments of the method of this invention in
which the rate of administration of the second or subsequent dose
of the therapeutic virus is controlled, and especially when the
virus is a replication-competent, mesogenic strain of Newcastle
Disease Virus, the amount of virus in the second or subsequent dose
is at least 3.times.10.sup.9 PFU per square meter of patient
surface area; at least 5.9.times.10.sup.9 PFU per square meter of
patient surface area; at least 1.2.times.10.sup.10 PFU per square
meter of patient surface area; at least 2.4.times.10.sup.10 PFU per
square meter of patient surface area; at least 4.8.times.10.sup.10
PFU per square meter of patient surface area; at least
9.6.times.10.sup.10 PFU per square meter of patient surface area;
at least 1.2.times.10.sup.11 PFU per square meter of patient
surface area; at least 1.44.times.10.sup.11 PFU per square meter of
patient surface area; or at least 1.96.times.10.sup.11 PFU per
square meter of patient surface area.
[0026] The volume, and hence the concentration, for a therapeutic
virus dose generally is not critical. Nevertheless, when choosing a
volume the rate of administration should be taken into account. If
the volume is too small, it may be difficult to infuse over a long
period of time. When administration is to take place over a time
period of thirty minutes or more, it has been found convenient to
dilute virus doses of less than 4.8.times.10.sup.10 PFU/m.sup.2 in
25 ml to 100 ml or even greater volumes of saline. For virus doses
of greater than 4.8.times.10.sup.10 PFU/m.sup.2 dilution in 50 ml
to 250 ml or even greater volumes of saline is convenient.
[0027] The invention will be better understood by reference to the
following examples, which illustrate but do not limit the invention
described herein. In the following examples the NDV used was a
triple-plaque purified attenuated (mesogenic) version of the MK107
strain of Newcastle Disease Virus, described more fully in
International Patent Publication WO 00/62735, published Oct. 26,
2000 (Pro-Virus, Inc.). The entire contents of WO 00/62735 and WO
94/25627 are hereby incorporated herein by reference.
EXAMPLES
Example 1
[0028] Adults with advanced solid tumors, good performance status
and adequate end-organ function were treated. PPMK107, a mesogenic
Newcastle disease virus strain, as disclosed in WO 00/62735, was
given intravenously 3 times per week for 1 week cycled every 4
weeks. Patients were given an initial desensitization dose of
1.2.times.10.sup.10 PFU/m.sup.2 followed by higher doses ranging
from 2.4 to 9.6.times.10.sup.10 PFU/m.sup.2. This approach
therefore used a "Single Step Desensitization". Doses 2-3 were
constant in each patient, but escalated by cohort (Table 1). In
this example, the first dose of 1.2.times.10.sup.10 PFU/m.sup.2 was
administered over 10 minutes, the doses of 2.4 to
4.8.times.10.sup.1 PFU/m.sup.2 was given over 10 minutes and the
dose of 9.6.times.10.sup.10 PFU/m.sup.2 was given over 10 to 20
minutes.
1TABLE 1 Dose Levels and Patient Number by Cohort Cohort Dose 1
Doses 2-3 Number of patients 1 1.2 .times. 10.sup.10 PFU/m.sup.2
2.4 .times. 10.sup.10 PFU/m.sup.2 4 2 1.2 .times. 10.sup.10
PFU/m.sup.2 4.8 .times. 10.sup.10 PFU/m.sup.2, 3 3 1.2 .times.
10.sup.10 PFU/m.sup.2 7.2 .times. 10.sup.10 PFU/m.sup.2, 5 4 1.2
.times. 10.sup.10 PFU/m.sup.2 9.6 .times. 10.sup.11 PFU/m.sup.2,
12
Example 2
[0029] Adults with advanced, solid tumors, good performance status
and adequate end-organ function were treated. PPMK107, a mesogenic
Newcastle disease virus strain, as disclosed in WO 00/62735, was
given intravenously over 30 minutes, 6 times in 2 weeks, cycled
every 21 days. 4 dose levels were studied. In each cohort, the
1.sup.st and 2.sup.nd doses were 1.times.10.sup.9 PFU/m.sup.2 and
1.2.times.10.sup.10 PFU/m.sup.2, respectively. Doses 3-6 were
constant in each patient, but escalated by cohort beginning at a
level of 2.4 10.sup.10 PFU/m.sup.2 (Table 2). This approach
therefore used a "2-Step Desensitization". Dose limiting toxicity
(DLT) was defined as any drug-related toxicity of grade 3/4 seen
during cycle 1.
2TABLE 2 Dose Levels and Patient Number by Cohort Number of Cohort
Dose 1 Dose 2 Doses 3-6 patients 1 1 .times. 10.sup.9 PFU/m.sup.2
1.2 .times. 10.sup.10 PFU/m.sup.2 2.4 .times. 10.sup.10 PFU/m.sup.2
3 2 1 .times. 10.sup.9 PFU/m.sup.2 1.2 .times. 10.sup.10
PFU/m.sup.2 4.8 .times. 10.sup.10 PFU/m.sup.2, 3 3 1 .times.
10.sup.9 PFU/m.sup.2 1.2 .times. 10.sup.10 PFU/m.sup.2 9.6 .times.
10.sup.10 PFU/m.sup.2, 4 4 1 .times. 10.sup.9 PFU/m.sup.2 1.2
.times. 10.sup.10 PFU/m.sup.2 1.2 .times. 10.sup.11 PFU/m.sup.2,
3
[0030] Results: Thirteen cancer patients have been enrolled (7
males; median age 58 years; cancer types: 5 colorectal; 2 each
breast, sarcoma, ovary; 1 each non-small cell lung, anal). First
dose toxicity consisted of flu-like symptoms lasting <72 hours,
all grade 2 or less, and less severe than those seen using
single-step desensitization and a first dose of 1.2.times.10.sup.10
PFU/m.sup.2 (Example 1). The improved safety profile of the 2-step
desensitization described in this example is best illustrated by
Table 3 below which compares the incidence of grade 3 adverse
events seen using these 2 different approaches. No DLTs have been
observed. Median number of cycles delivered=2 (range <1 to 8).
Of 10 patients evaluable for response, five had stable disease, and
five had progressive disease.
3TABLE 3 Comparison of Incidence of Grade 3 (Severe) Adverse Events
Seen in Patients Administered the Two-Step Desensitization of
Example 2 versus the One-Step Desensitization of Example 1.
Incidence of Grade 3 (Severe) Two Step Single-Step Desensitization
Desensitization (N = 13 patients, (N = 24 patients, Adverse Event
Example 2) Example 1 Fatigue 0% 38% Fever 0% 13% Nausea 0% 8%
Vomiting 0% 8%
Example 3
[0031] Adults with advanced, incurable solid tumors, good
performance status and adequate end-organ function are treated.
PPMK107, a mesogenic Newcastle disease virus strain, as disclosed
in WO 00/62735, is given intravenously, 6 times in 2 weeks, cycled
every 21 days. The first dose is given over 3 hours and subsequent
doses are given over 1 hour. Three different dose levels are
included in this example. At each dose level, the 1.sup.st dose is
a desensitizing dose for the higher doses. Doses 2-6 were constant
in each patient (Table 4). This approach therefore uses a "Single
Step Desensitization"
4TABLE 4 Dose Levels Time of Time of Infusion Infusion Dose for for
Level Dose 1 Dose 1 Doses 2-6 Doses 2-6 1 1.2 .times. 10.sup.10
PFU/m.sup.2 3 hours 2.4 .times. 10.sup.10 PFU/m.sup.2 1 hour 2 2.4
.times. 10.sup.10 PFU/m.sup.2 3 hours 4.8 .times. 10.sup.10
PFU/m.sup.2, 1 hour 3 2.4 .times. 10.sup.10 PFU/m.sup.2 3 hours 1.2
.times. 10.sup.11 PFU/m.sup.2, 1 hour
* * * * *